1. Field of the Invention
The present invention relates generally to .beta.-amyloid peptide and its toxic effects with respect to neural cells. More particularly, the present invention relates to neural cells which express low-affinity nerve growth factor receptor and methods for increasing the resistance of such cells to .beta.-amyloid peptide toxicity.
2. Description of Related Art
The publications and other reference materials referred to herein to describe the background of the invention and to provide additional detail regarding its practice are hereby incorporated by reference. For convenience, the reference materials are numerically referenced and grouped in the appended bibliography.
A hallmark of Alzheimer disease is an early and severe telencephalic cholinergic deficit preferentially involving temporal lobe and limic cortical structures, hippocampus, and amygdala (1-3). The degree of cholinergic decrement correlates well with the severity of dementia (3). Decreases in other neurotransmitters occur to a lesser extent (3), and such deficits are not proportional to the magnitude of intellectual impairment (4).
Virtually all of the cholinergic innervation of the outer cerebral mantle derives from the basal nuclear complex, which is composed of the medial spetal nucleus, nuclei of the diagonal band, magnocellular preoptic area, ventral pallidum/substantial innominata region, nucleus basalis, and nucleus of the ansa lenticularis (5-7). This constellation of cholinergic neutrons undergoes degeneration in Alzheimer disease and in at least 13 other diseases in which dementia features prominently (8-10), leading to the question of what characteristic renders these cells selectively vulnerable in those conditions (8).
.beta.-amyloid peptide (.beta.AP) has been shown to be neurotoxic in primary neural cell cultures (11). Moreover, .beta.AP has been implicated in the pathogenesis of Alzheimer disease by the discovery of mutations in the .beta.-amyloid precursor protein gene in a small percentage of familial Alzheimer disease patients (12). In addition, the extent of neuronal loss in the basal forebrain of patients with Alzheimer disease is positively correlated with the degree of .beta.-amyloid accumulation in that region (13).
However, the finding of .beta.AP neurotoxicity does not explain the predisposition of the cholinergic neurons of the basal nuclear complex to degeneration in Alzheimer disease. These neurons express the highest levels of p75.sup.NTR, the low-affinity nerve growth factor receptor (NTR), in the brain; in contrast, neurons of the other major cholinergic complex in the mammalian brain, the pedunculopontine and laterodorsal tegmental nuclei, neither express p75.sup.NTR nor undergo degeneration in Alzheimer disease (14, 15). p75.sup.NTR expression has been demonstrated to enhance apoptosis in the unbound state, whereas, when p75.sup.NTR is bound by nerve growth factor (NGF) or monoclonal antibody, cell survival is enhanced (16).
In view of the above, there is a continuing need to further investigate NTR and its relationship to .beta.-amyloid peptide toxicity with respect to neural cells involved in Alzheimer disease.